tbuckley/cabot-search huggingface dataset:
<i>MBD4</i> deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients: A retrospective study.
Authors: Mathilde Saint-Ghislain, Lionnel Geoffrois, Lauris Gastaud, Thierry Lesimple, Sylvie Negrier, Nicolas Penel, Jean Emmanuel Kurtz, Yannick Le Corre, Caroline Dutriaux, Sophie Gardrat, Raymond Barnhill, Alexandre Matet, Nathalie Cassoux, Toulsie Ramtohul, Vincent Servois, Pascale Mariani, Sophie Piperno-Neumann, Manuel Rodrigues
Journal: Journal of Clinical Oncology (2022)

e21601 Background: MBD4 encodes a glycosylase implicated in repair of lesions induced by DNA deamination and its inactivation in tumors is associated with a hypermutated phenotype. Uveal melanoma (UM) is a rare but aggressive form of melanoma carrying an extremely low mutation burden. Although metastatic UM (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI. Since then, other MBD4-inactivated UMs, acute myeloid leukemias, colorectal adenocarcinomas, gliomas and spiradenocarcinoma cases have been reported. Methods: Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients. Results: Three hundred mUM patients were analyzed. Median follow-up was 17.3 months. Ten objective responses and 20 stable disease for &gt; 12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (CB; i.e. responder patients and stable disease) rate of 10%. Median progression-free survivals (PFS) in patients without and with CB were 3.1 and 16.3 months, respectively (p &lt; 0.0001). Of the 134 tumors sequenced for MBD4, five (3.7%) were mutated. MBD4 inactivation was associated with higher mutation burden (179 to 643 variants versus a median of 16 in MBD4 wild-type), better objective response rate as 60% of MBD4m versus 4% of MBD4-wild type patients responded (Fisher’s exact p-test = 0.0009). Median PFS was 4.0 months in MBD4-wild type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median overall survival was 16.6 months in MBD4-wild type and unreached in MBD4m patients (HR = 0.11; p = 0.004). Conclusions: In mUM patients, MBD4 mutation is highly predictive for response to ICI, PFS and overall survival benefit. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM and other tumor types where MBD4 mutations are reported.
Subcutaneous nivolumab versus intravenous nivolumab in patients with previously treated, advanced, or metastatic clear cell renal cell carcinoma.
Authors: Matias Rodrigo Chacon, Hernan J. Cutuli, Sergio Bracarda, Marco Maruzzo, Maria Teresa Bourlon, Carmel Jacobs, Begoña Pérez-Valderrama, Ignacio Magri, Martin Richardet, Piotr Centkowski, Simon Yuen Fai Fu, Pablo Gurman, Srivani Konduri, Zhuoxin Yu, Heather Vezina, Saby George, Laurence Albiges
Journal: Journal of Clinical Oncology (2022)

TPS4621 Background: Nivolumab (NIVO), a programmed death-1 immune checkpoint inhibitor, has demonstrated clinical efficacy across patients with different tumor types, including clear cell renal cell carcinoma (ccRCC), when administered via IV infusion. As an alternative to IV infusion, subcutaneous (SC) administration alleviates the need for IV ports, thereby lowering the risk of associated complications such as infections and phlebitis. SC formulation also reduces the time for dose preparation and administration, which may decrease overall treatment burden and reduce patient time in the clinic, benefiting patients and healthcare providers and improving overall healthcare resource utilization. SC-administered NIVO consists of NIVO co-formulated with the recombinant human hyaluronidase PH20 enzyme (NIVO + rHuPH20), which aims to increase the dispersion and absorption of NIVO within the SC space. SC NIVO + rHuPH20 was shown to be safe and well tolerated in a phase 1/2 study, warranting further investigation (Lonardi S et al. J Clin Oncol 2021;39(suppl 15):2575). Methods: CheckMate 67T is a multicenter, randomized, open-label, phase 3 study that will evaluate the noninferiority of SC NIVO + rHuPH20 versus IV NIVO in patients with advanced or metastatic ccRCC who have progressed after receiving ≤ 2 prior systemic treatment regimens. Key inclusion criteria are age ≥ 18 years, histologically confirmed advanced or metastatic ccRCC, measurable disease by RECIST v1.1 within 28 days prior to randomization, and a Karnofsky performance status ≥ 70. Key exclusion criteria are untreated symptomatic metastases to the central nervous system, other malignancy, autoimmune diseases, HIV-positive status with AIDS-defining infection within past year or current CD4 count &lt; 350 cells/μL, other serious or uncontrolled disorders including severe, acute SARS-CoV-2 infection, and prior treatment with immune checkpoint inhibitors, other T-cell–targeting antibody drugs, or live attenuated vaccines within 30 days of first study treatment. At least 454 eligible patients will be randomized to receive SC NIVO + rHuPH20 or IV NIVO. The primary objectives are to demonstrate pharmacokinetic (PK) noninferiority of SC NIVO versus IV NIVO, as measured by time-averaged serum concentration over the first 28 days (Cavgd28) and trough serum concentration at steady state (Cminss) (co-primary endpoints). Secondary endpoints include objective response rate by blinded independent central review, additional PK parameters, safety, efficacy, and immunogenicity of SC NIVO and IV NIVO. This study is currently enrolling patients globally. Clinical trial information: NCT04810078.
Inferior survival outcomes with concomitant immune checkpoint inhibitors and chronic opioid use.
Authors: Aaron Varghese, Steven Gallo, Deanna Argentieri, Bethany W Harvey, Kayla Catalfamo, Kristopher Attwood, Emese Zsiros
Journal: Journal of Clinical Oncology (2022)

e14564 Background: Immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote immune recognition of tumor cells to facilitate their elimination. Opioids are a major facet of pain management in cancer patients. Since chronic opioid use results in immunosuppression, the purpose of this study was to evaluate the survival outcomes of cancer patients on concurrent ICI and opioid therapy. Methods: This single-institute retrospective study from an NCI-designated comprehensive cancer center evaluated all patients in the primary or recurrent setting who underwent ICI therapy (anti-PD-1/PD-L1/CTLA-4) from 1 January 2020 to 18 June 2021. Demographic, clinicopathologic, and co-morbidity data were obtained from electronic medical records and the New York State Cancer Registry data. The New York State Prescription Monitoring Program was used to collect data about opioid prescriptions filled by patients from 30 days prior to and 30 days after the end of ICI therapy. Patient characteristics were analyzed with the Mann-Whitney U or chi-square tests. Survival analyses were performed using the Kaplan-Meier and Cox model regression, adjusting for relevant clinical factors. Results: A total of 869 patients were evaluable based on inclusion criteria and data availability. Most patients (77.15% chronic users and 64.62% occasional users) had stage III/IV disease. The most represented services included: gynecology (11.54%), soft tissue/melanoma (14.13%), thoracic (38.75%), urology (11.9%). Comorbidities did not vary between the two groups. Pre-treatment median opioid consumption was higher in the chronic users compared to occasional users (240 oral morphine equivalents (OME) vs 120, p = 0.03). Total opioid prescriptions filled was significantly higher for chronic users compared to occasional users (4275.0 vs 520.1 OME, p &lt; 0.001). Chronic users were more likely to be on an additional anti-neoplastic agent (64% vs 44.07% for occasional users). Occasional users had significantly longer progression free (44.7 vs 16.0 months, p &lt; 0.001) and overall (42.7 vs 16.2 months, p &lt; 0.001) survival. When controlling for age, stage, and concurrent therapy, chronic opioid use retained a significantly negative association with PFS and OS. Conclusions: Patients on ICI therapy in the primary and recurrent setting who chronically use opioids exhibit significantly decreased PFS and OS compared to the occasional user cohort. This study provides evidence that chronic opioid use during ICI therapy results in inferior clinical outcomes.
Using all Gene Families Vastly Expands Data Available for Phylogenomic Inference
Authors: Megan L. Smith, Dan Vanderpool, Matthew W. Hahn
Journal: Molecular Biology and Evolution (2022)

Traditionally, single-copy orthologs have been the gold standard in phylogenomics. Most phylogenomic studies identify putative single-copy orthologs using clustering approaches and retain families with a single sequence per species. This limits the amount of data available by excluding larger families. Recent advances have suggested several ways to include data from larger families. For instance, tree-based decomposition methods facilitate the extraction of orthologs from large families. Additionally, several methods for species tree inference are robust to the inclusion of paralogs and could use all of the data from larger families. Here, we explore the effects of using all families for phylogenetic inference by examining relationships among 26 primate species in detail and by analyzing five additional data sets. We compare single-copy families, orthologs extracted using tree-based decomposition approaches, and all families with all data. We explore several species tree inference methods, finding that identical trees are returned across nearly all subsets of the data and methods for primates. The relationships among Platyrrhini remain contentious; however, the species tree inference method matters more than the subset of data used. Using data from larger gene families drastically increases the number of genes available and leads to consistent estimates of branch lengths, nodal certainty and concordance, and inferences of introgression in primates. For the other data sets, topological inferences are consistent whether single-copy families or orthologs extracted using decomposition approaches are analyzed. Using larger gene families is a promising approach to include more data in phylogenomics without sacrificing accuracy, at least when high-quality genomes are available.
Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer
Authors: Emma Kurz, Carolina Alcantara Hirsch, Tanner Dalton, Sorin Alberto Shadaloey, Alireza Khodadadi-Jamayran, George Miller, Sumedha Pareek, Hajar Rajaei, Chirayu Mohindroo, Seyda Baydogan, An Ngo-Huang, Nathan Parker, Matthew H.G. Katz, Maria Petzel, Emily Vucic, Florencia McAllister, Keri Schadler, Rafael Winograd, Dafna Bar-Sagi
Journal: Cancer Cell (2022)
Virtual ChIP-seq: predicting transcription factor binding by learning from the transcriptome
Authors: Mehran Karimzadeh, Michael M. Hoffman
Journal: Genome biology (2022)

Abstract Existing methods for computational prediction of transcription factor (TF) binding sites evaluate genomic regions with similarity to known TF sequence preferences. Most TF binding sites, however, do not resemble known TF sequence motifs, and many TFs are not sequence-specific. We developed Virtual ChIP-seq, which predicts binding of individual TFs in new cell types, integrating learned associations with gene expression and binding, TF binding sites from other cell types, and chromatin accessibility data in the new cell type. This approach outperforms methods that predict TF binding solely based on sequence preference, predicting binding for 36 TFs (MCC&gt;0.3).
Prognosis and factors associated with disseminated nocardiosis: a ten-year multicenter study
Authors: Sarah Soueges, Kevin Bouiller, Elisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Catherine Chirouze, Veronica Rodriguez-Nava, Oana Dumitrescu, Claire Triffault-Fillit, Anne Conrad, David Lebeaux, Elisabeth Hodille, Florent Valour, Florence Ader
Journal: Journal of Infection (2022)
Tisagenlecleucel for secondary CNS lymphoma, a case series.
Authors: Shivtaj Mann, Armaan Dhaliwal, Muhammad Husnain, Abhijeet Kumar, Daniel O. Persky
Journal: Journal of Clinical Oncology (2022)

e19507 Background: Secondary CNS lymphoma (SCNSL) in setting of relapsed, refractory (R/R) B cell lymphoma has unmet needs as this disease state has a poor prognosis with a reported median survival of 2 to 5 months. Historically, the mainstay of treatment for SCNSL in setting of R/R B cell lymphoma included high dose methotrexate, whole brain radiation (WBRT), and/or chemotherapy followed by autologous stem cell transplant. More recently, chimeric antigen receptor (CAR)-T cell therapy has gained attention as a new modality of therapy for patients with R/R SCNSL. The first two CAR-T cell products to gain FDA approval for R/R B cell lymphoma were Axicabtagene ciloleucel and Tisagenlecleucel. In the initial studies for these products, patients with SCNSL were excluded due to concerns for immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS). Retrospective data has shown that patients with R/R SCNSL treated with Axicabtagene ciloleucel or Tisagenlecleucel could achieve high response rates; however, the data on the durability of response remains unclear. Recently, Lisocabtagene maraleucel, another CAR-T cell product, was approved for the treatment of R/R B cell lymphoma. The TRANSCEND trial which led to Lisocabtagene maraleucels approval did not exclude patients with SCNSL; however, only 3% of the patients had SCNSL. As such, literature on the durability of response of CAR-T cell therapy in R/R SCNSL still remains sparse. Here, we share our single institution experience of patients with R/R SCNSL treated with Tisagenlecleucel, an anti- CD19CAR-T cell therapy. Methods: For this observational study, patients with R/R SCNSL were identified and placed on a follow up list. Data was collected from May 2021 till December 2021. Data was analyzed for incidence of ICANS, CRS, and for duration of response. Results: A total of 3 patients with SCNSL were identified and treated at our center with Tisagelecleucel. One patient achieved complete response 30 days post CAR-T therapy but the day +100 imaging revealed progression of disease and was placed on subsequent line of therapy. One patient had partial response with progression of disease noted on day +60 imaging and died from complications of disease progression. One patient died from complications of CNS toxicity after receiving CAR-T therapy. Two patients had ICANS grade 4 and CRS grade 1 toxicities. One patient had no CNS or CRS toxicity. Conclusions: Our series is limited by the number of patients; however, suggests that though CAR-T therapy may result in disease response in R/R SCNSL the duration of response may be limited and that such patients may require other therapies such as autologous stem cell transplant to improve long term prognosis.
Unnatural Amino‐Acid‐Based Star‐Shaped Poly(<scp>l</scp>‐Ornithine)s as Emerging Long‐Term and Biofilm‐Disrupting Antimicrobial Peptides to Treat <i>Pseudomonas aeruginosa</i>‐Infected Burn Wounds
Authors: Miao Pan, Chao Lu, Maochao Zheng, Wen Zhou, Fuling Song, Weidong Chen, Fen Yao, Daojun Liu, Jianfeng Cai
Journal: Advanced Healthcare Materials (2022)
Phase I trial combining pembrolizumab and doxorubicin in patients with metastatic triple negative breast cancer.
Authors: Yuan Yuan, Xuan Ge, Susan Elaine Yost, Jin Sun Lee, Paul Henry Frankel, Christopher Ruel, Yujie Cui, Mireya Murga, Aileen Tang, Norma Martinez, Misagh Karimi, George Somlo, Joanne E. Mortimer, James Ross Waisman
Journal: Journal of Clinical Oncology (2022)

e13071 Background: Pembrolizumab (pembro) in combination with chemotherapy (chemo) has recently become standard of care in patients with programmed death-ligand 1 (PD-L1) positive metastatic triple negative breast cancer (mTNBC). Optimal chemo partner with pembro remains debatable. The current phase I study evaluated the safety and efficacy of doxorubicin (dox) + pembro in anthracycline-naïve mTNBC patients (NCT02648477). Methods: Patients with mTNBC, no prior anthracycline, and ≤2 lines of prior chemo for metastatic disease were enrolled. Patients received pembro 200mg IV and 50-60 mg/m 2 dox IV every 3 weeks x6, followed by pembro maintenance until progression or unacceptable toxicity. The primary objectives were safety and objective response rate (ORR per RECIST 1.1). For the safety lead-in, we employed a 3-at-risk rolling design. Results: Ten patients were accrued between March 2016 and November 2019. The trial stopped early due to poor accrual. The first 3 patients received dox at 50mg/m2 without dose limiting toxicities and dose was escalated to 60mg/m2 for the remaining patients. Median age was 62 years (range 41-87). Grade ≥ 3 AEs were: 4 neutropenia, 2 dyspnea, 2 fatigue, 1 oral mucositis, 1 hyponatremia, 1 acidosis, 1 alkalosis, 1 hypotension and 1 respiratory failure. One patient (age 87) received 1 dose of therapy, developed neutropenia and respiratory failure which led to death, and was not eligible for response assessment. 1 patient did not have RECIST measurable disease. Two patients had dose delay (1 G3 neutropenia and 1 G2 upper airway infection). 1 patient had dose reduction due to G3 fatigue. Immune toxicity was consistent with known pembro toxicity. Of 9 evaluable patients, responses were : 1 CR, 3 PR, 2 UPR, 2 SD and 1 PD, which translated to a best ORR of 67% (95% CI, 13.7%, 78.8%). CBR at 6 mo was 56% (95% CI 21.2%, 86.3%). Median follow-up time was 34.6 mo (range 14.5 - 45.4 mo). Median PFS was 5.2 mo (95% CI 4.7, NA); and median OS was 15.6 mo (95% CI 13.3, NA). Eight patients had PD-L1 (22C3) testing: 4 positive and 4 negative. No association between the PD-L1 status and response was observed. Conclusions: The combination of pembro+dox was well tolerated and had modest activity in anthracycline-naïve patients with mTNBC. The finding needs to be further confirmed with future study. Clinical trial information: NCT02648477.
Safety and survival outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with lutetium-177–prostate-specific membrane antigen (<sup>177</sup>Lu-PSMA) after radium-223 (<sup>223</sup>Ra): Interim analysis of the RALU study.
Authors: Kambiz Rahbar, Markus Essler, Matthias Eiber, Christian la Fougère, Vikas Prasad, Wolfgang P. Fendler, Philipp Rassek, Ergela Hasa, Helmut Dittmann, Ralph A. Bundschuh, Kim M. Pabst, Milena Kurtinecz, Per Sandstrom, Frank Verholen, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2022)

5040 Background: 223 Ra and 177 Lu-PSMA both prolong overall survival (OS) in different mCRPC settings. Previous data from the observational REASSURE (Sartor O, et al. 2021) and WARMTH (Ahmadzadehfar H, et al. 2021) studies suggested the feasibility of sequencing 223 Ra and 177 Lu-PSMA therapies. Here we used data from the observational, retrospective RALU study to further examine the safety and clinical outcomes of sequential 223 Ra/ 177 Lu-PSMA therapy in pts with mCRPC. Methods: This interim analysis investigated the baseline characteristics, safety (primary endpoint) and OS (secondary endpoint) in pts who received 177 Lu-PSMA after 223 Ra using retrospective data collected in German centers. Results: Data from 49 pts were available for this interim analysis. At baseline, before the start of 177 Lu-PSMA, 73% of pts were Eastern Cooperative Oncology Group performance status (ECOG PS) 1 and 27% ECOG PS 2. Visceral metastases were present in 31% of pts. Median prostate-specific antigen (PSA) and alkaline phosphatase (ALP) were 287 ng/ml and 142 U/L, respectively (Table). 70% of pts received ≥4 life-prolonging therapies prior to 177 Lu-PSMA, with abiraterone acetate (80%), enzalutamide (67%) and docetaxel (92%) being the most frequently used. 74% of pts received ≥5 223 Ra injections. Pts received either PSMA-617 (67%) or PSMA I&amp;T (33%): 65% of pts received 1–4 cycles and 33% received 5–6 cycles. Median duration of 177 Lu-PSMA therapy was 4.9 months (m) (0–57.1). Median time from the last 223 Ra dose to first 177 Lu-PSMA dose was 9.3 m (0.9–41.9). Any grade treatment-emergent adverse events (TEAEs) from the start of 177 Lu-PSMA therapy to 30 days of follow-up occurred in 91.8% of pts, and serious TEAEs in 20% of pts. Grade 3-4 hematologic laboratory abnormalities up to 90 days post- 177 Lu-PSMA occurred in 34.7% of pts for anemia, 12.8% for thrombocytopenia and 2.0% for neutropenia. No grade 5 toxicities occurred. 39% of pts had ≥30% decline in PSA during 177 Lu-PSMA treatment. Median OS was 12.6 m (95% CI 8.8–16.1) from the start of 177 Lu-PSMA therapy. Conclusions: In this real-world retrospective analysis of selected pts with advanced mCRPC, the 223 Ra/ 177 Lu-PSMA treatment sequence was clinically feasible and well tolerated. [Table: see text]
Repeat large panel genomic sequencing identifies actionable alterations and characterizes the genomic landscape in patients with metastatic solid tumors.
Authors: Niamh Coleman, Timothy P. DiPeri, Daniel Nguyen, Aung Naing, Sarina Anne Piha-Paul, Apostolia Maria Tsimberidou, Xiaofeng Zheng, Amber Johnson, Wanlin Wang, Kenna R. Shaw, Ecaterina Elena Dumbrava, Siqing Fu, Jordi Rodon Ahnert, David S. Hong, Vivek Subbiah, Timothy A. Yap, Rajyalakshmi Luthra, Keyur P. Patel, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2022)

3076 Background: The implementation of genomic profiling with next generation sequencing has revolutionized the field of precision oncology. Comprehensive genomic testing of tumors to identify actionable genomic alterations is now commonly performed in the care of patients with advanced/metastatic disease. Although the genomic profile of tumors has been shown to evolve with progression and intervening treatments, the role of repeat genomic testing is not well established. We sought to determine the evolution of actionable genomic alterations in patients undergoing repeat genomic testing on the same comprehensive genomic panel. Methods: We retrospectively examined the molecular profiles and medical records of 262 patients with metastatic solid tumors treated in MD Anderson who underwent genomic testing on the same panel (Oncomine, Thermo Fisher) for the detection of somatic mutations in the coding sequence of 143 cancer-related genes, on at least 2 separate occasions. Genomic alterations were reviewed by a central Precision Oncology Decision Support (PODS) team in order to provide annotations at the alteration level on the functional significance. Results: 262 patients underwent repeat genomic testing using the same genomic panel on samples collected at different time points from July 2010 to Dec 2021 across tumor types. Changes in alterations (gain or loss) were identified on repeat testing in most patients (66%) We then specifically assessed changes in alterations that were categorized as actionable if annotated by the PODS team at the time of reporting. A gain or loss of an actionable alteration was detected in 38% (100/262) patients. New actionable alterations were frequently identified (73%; 73/100), while 41% had loss of an actionable alteration (41/100). 14% had both loss and gain of actionable alteration on repeat testing; 58% had new actionable alteration identified alone; 27% had loss of actionable alteration only. Actionable alterations identified on repeat testing included alterations in PI3K/AKT (27%), EGFR (15%), and MAPK (16%). On repeat testing, changes in ³2 actionable alterations were frequently identified in the same test (43%). Conclusions: Repeat large panel genomic testing identifies both gain and loss of actionable alterations in patients with advanced metastatic cancers. Actionable aberrations frequently co-exist with alterations in a variety of other genes, which highlights the complexities of treating patients with metastatic cancer on progression of disease and suggests that tailored combination strategies may be necessary in these patients.